Bone generation and maintenance involves osteoblasts, osteoclasts, and osteocytes which originate from unique precursors and rely on key growth factors for differentiation. However, there is an incomplete understanding of bone forming cells during wound healing.
Many substances such as cytokines, chemokines, and other effectors are associated with wound repair. One such substance, hCAP-18, has multiple effects on monocytes including the induction of migration (De et al. 2000; Zhang et al. 2009) and differentiation of monocytes to dendritic cells (DCs) (Davidson et al. 2004). hCAP-18 is the only human member of the cathelicidin family of antimicrobial peptides known to date (Sorensen et al 1997). LL-37, the proteolytically (proteinase 3) active product of hCAP-18, has been demonstrated to mediate a wide variety of immune and inflammatory functions, including wound repair. Release of LL-37 increases during inflammation, including that resulting from trauma and bone fracture. Growth factors involved in the process of wound healing were shown to induce LL-37 expression (Sorensen et al. 2003). In vitro, LL-37 was shown to activate endothelial cells resulting in increased proliferation and formation of vessel-like structures, while in vivo cathelicidin (CRAMP)-deficient mice showed decreased vascularization during wound repair (Kocaulla et al. 2003). LL-37 promotes re-epithelialization of healing skin (Tjabring a et al. 2003) and anti-LL-37 antibodies inhibit re-epithelialization of skin wounds (Heilborn et al. 2003). Furthermore, LL-37 induces migration of human peripheral blood monocytes, neutrophils, CD4+ T cells, and mast cells (De et al. 2000; Zhang et al. 2009; Agerberth et al. 2000; Niyonsaba et al. 2002) and influences the expression of over 40 genes in murine RAW 264.7 macrophage cells, some of which are involved in bone formation, including the bone morphogenetic protein (BMP) 1, BMP-2, and BMP-8a (Scott et al. 2002).
Bone generation, maintenance and healing are complicated processes in which osteoblasts, osteoclasts, and osteocytes play important roles. Osteoblasts, which are derived from mesenchymal stem cells (MSCs) (Nuttall & Gimble 2004), express marker genes for bone sialoprotein (BSP) and osteocalcin (OC). Osteoclasts, which are derived from monocytes by the action of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL), affect bone resorption by removing its mineralized matrix and breaking up the organic bone (Lacey et al. 1998). In addition to these two types of cells, the bone contains osteocytes which are trapped in the bone matrix and cease to generate osteoid and mineralized matrix. The function of osteocytes is considered as inactive osteoblasts or bone lining cells (Manolagas 2000) that undergo programmed cell death (Manolagas 2000; Jilka et al. 1998). Although much is known about the role of osteoblasts and osteoclasts in new bone formation and remodeling of existing bone, less is known about the role of these or other cells in bone repair and wound healing. (Khosla et al. 2008) Therefore, discovery and characterization of novel bone-forming cells involved in bone formation is desired to meet the unfilled clinical needs of increasing bone mass in bone injuries, malformations and diseases is desired.